Monday, August 6, 2012

Curing Chronic Hepatitis C: The New World of Antivirals

A U G U S T 2 0 1 2 • G I & H E PATOLOGY NEWS
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Curing Chronic Hepatitis C: The New World of Antivirals


Currently, 170 million persons worldwide and 3.7 million in the United States are infected with hepatitis C virus (HCV). Unfortunately, 75% of infected U.S. residents remain undiagnosed and 25% already have cirrhosis.

Because of increased cure rates with new therapy, HCV screening of “baby boomers” (age 46-64) followed by treatment is cost effective and is now recommended by the CDC.

If we were fortunate enough to find 100% of infected persons and treat them with 80% effective therapy, we could decrease HCV-liver related death by 70% (Davis GL, et al. Gastroenterology 2010). To achieve this, “a new kind of thinking is essential…” (Albert Einstein); this new kind of thinking is the utilization of direct acting antiviral (DAA) therapy.

The past history of HCV therapy has been nonspecific and side effect–laden, involving long treatments with low cure rates. But the future promises DAAs with fewer side effects and 80%-100% cure rates in as little as 12 weeks.

Although numerous targets exist, the three with the most promise are:

Protease inhibitors
The current standard of care for treatment of genotype 1 HCV infection is responseguided therapy with a linear protease inhibitor (telaprevir or boceprevir), pegylated interferon (PEG), and ribavirin (RBV), which achieves a 67%-75% sustained virologic response (SVR; 99.1% of the time this equated to cure). TMC435, an oral, once-daily macrocyclic protease inhibitor, achieved 86%, 85%, 75%, and 51% SVR in naive, relapsers, partial responders, and null responders, respectively (Zeuzem S, et al. EASL Abstract 2). Ritonovir boosted danaprovir plus PEG and RBV for 24 weeks achieved 96% SVR in naive genotype 1/4 patients, and IL28B CC patients who achieve an eRVR may need as little as 12 weeks of triple therapy (Everson, G, et al. DAUPHINE EASL 1177).

Polymerase inhibitors
These drugs target either the active site or one of the four allosteric sites of the NS5B polymerase. The pangenotypic active site inhibitor, GS-7977, in combination with RBV for 12 weeks achieved 100% SVR in naive and 80% SVR in prior treatment failure genotype 2/3 patients. GS-7977 combined with PEG/RBV for 12 weeks in naive genotype 1 patients achieved a 90% SVR, and interferon free, an 88% SVR4, although this interferon-free regimen was ineffective against genotype 1 prior null responders (Kowdley K, et al. ATOMIC, EASL 1; Gane EJ, et al. ELECTRON EASL 1113).

NS5a inhibitors
These agents play an integral role in the replication complex. Daclatasvir, a pangenotypic once-daily dosed NS5a inhibitor, in combination with PS-7977 with or without RBV for 24 weeks, resulted in 100% SVR4 (Sulkowski M, et al. EASL Abstract 1422). Daclatasvir has also been combined with the BID-dosed protease inhibitor, Asunaprevir, for 24 weeks resulting in 90% SVR in genotype 1b but only 36% SVR in genotype 1a prior null responders (Suzuki F, et al. EASL Abstract 14; Lok AS, et al., NEJM 2012;366:216).

An HCV treatment revolution has begun.
HCV screening of all baby boomers should identify 1,000,000 new cases of infection. Over the next decade, DAA therapy will evolve. First, second-generation protease inhibitors will be combined with PEG and RBV; second, interferon-free therapy for genotype 2 and 3 patients will emerge. Then pangenotypic NS5a inhibitors will enter the market, followed by numerous interferonfree multidrug cocktails that will continually evolve. But interferon-free effective therapy for all genotypes will likely not be available for at least 5-7 years.

We stand poised at the precipice of possibility to transform the tragedy of liver failure into the triumph of SVR as HCV falls victim to our ongoing revolution, one patient at a time. ■

JACQUELINE G. O’LEARY, M.D., M.P.H., is Director, Inpatient Liver and Transplant Unit, Baylor University Medical Center, Dallas.

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